Many drugs that are water soluble and easily absorbed from the gastrointestinal track could be more advantageously formulated as controlled release once daily oral dosage forms instead of as immediate release dosage forms. Since a standard immediate release formulation is one that is designed to release the drug immediately upon dissolution in the gastrointestinal tract, there are at least two reasons why the switch to controlled release dosage forms would be beneficial. First, pertaining particularly to oral delivery, drugs ingested are passed through the gastrointestinal tract within 24 hours and sometimes in a few hours after ingestion. Second, pertaining to oral and parenteral delivery, the half life of most drugs is less than a day and usually no more than a few hours. Thus, it is very difficult for a standard immediate release single oral dose of a drug to be effective for more than 24 hours and in most cases more than several hours.
Naproxen, for example, is a propionic acid derivative ((S)-6-methoxy-methyl-2-naphthaleneacetic acid), non-steroidal, anti-inflammatory drug (NSAID) that exhibits analgesic and antipyretic properties. Naproxen represents pharmaceutically active compounds which (a) are water soluble and easily absorbed from the gastrointestinal track; (a) would be advantageous to be administered once a day instead of multiple times a day; and (c) are administered to a wide range of patients where an analgesic effect due to the inhibition of inflammation is desired. Many of the effects of naproxen are associated with the inhibition of prostaglandin synthesis and in particular cyclo-oxygenase (COX), a family of enzymes (COX 1 and COX 2 seem to currently be the most medically important), that catalyze the formation of prostaglandin precursors from arachidonic acid (Simmons, D. L. et al., Pharmacol. Rev. 2004, 56, pp. 387-437). Inhibition of COX 2 is believed to be effective in blocking the arachidonic acid metabolic pathway that is most responsible for pain and inflammation. Naproxen is used to relieve mild to moderately severe pain in rheumatoid arthritis, osteoarthritis and other inflammatory conditions.
Plasma naproxen concentrations of 30-90 μg/mL are reportedly required for anti-inflammatory or analgesic effects. Plasma naproxen levels between 30-70 μg/mL (Sevelius, H. et al., Br. J. Clin. Pharmacol. 1980, 10, pp. 259-263) have been reported to reduce post partum pain. Pain in patients with rheumatoid arthritis suggested that pain reduction in this condition occurred at plasma naproxen levels above 50 μg/mL (Day, R. O. et al., Clin. Pharmacol, Ther. 1982, 31, pp. 733-740). Thus, while the rate of absorption may affect the onset of analgesic activity, continued plasma levels of the drug are likely to be important in maintaining analgesia.
Examples of extended release formulations aimed at slowing release of drug as it travels through the gastrointestinal tract include those developed by Elan, Depomed, Alza, Biovail, Pennwest and Kos Pharmaceuticals. These drug delivery systems are based on polymer coatings, hydrogels, polymer foams, osmotic pressure, and other technologies (for a review, see Rosen, H. & T. Arbribat, 2005, Nat. Rev. Drug Discovery, published online Apr. 22, 2005, doi:10.1038/nrd1721). Other research has focused on the development of prodrugs designed to improve physicochemical, biopharmaceutical or pharmokinetic properties of drugs, including controlling or extending drug release in the body (for a review, see J. Rautio, et al., 2008, Nat. Rev. Drug Discovery Volume 7, March 2008, 255-270).
Notwithstanding the technical advances referred to above, a single dose of an immediate or extended release orally delivered formulation of a drug is almost never effective for at least a day, save a handful of drugs that have very long half lives. Thus, there is a need in the art to develop drug compositions and methods of manufacture that are able to extend the delivery of a single drug dose to beyond one day, and preferably to multiple days. This invention addresses those needs.